Project Summary/Abstract Longevity appears to be strongly affected by genetic and cellular factors. The FOXO3 gene that encodes the transcription factor forkhead box O-3 (FOXO3) has been consistently linked to increased human lifespan. Aging is typically accompanied by gradual brain atrophy and neurocognitive decline, but the cellular mechanisms underlying the aging process are still unclear. The proposed study seeks to understand how aging at the cellular level, as characterized by telomere shortening and altered telomerase activity, is related to longevity and brain aging. We hypothesize that the protective FOXO3 gene variant is associated with decelerated brain aging, and suggest that a slower rate of brain aging is also linked to greater telomerase activity and telomere length in peripheral blood leukocytes (PBL). Brain volume and function will be cross-sectionally assessed by structural magnetic resonance imaging (MRI) and resting-state functional connectivity (RSFC) MRI, respectively, in 100 male and female Kuakini Honolulu Heart Program (Kuakini HHP) Offspring study participants. Regional brain atrophy and disrupted RSFC will serve as indices of brain aging and will be examined for associations with FOXO3 genotype and PBL telomerase activity and telomere length. Additionally, we will investigate whether differences in RSFC associated with FOXO3 genotype, telomerase activity or telomere length, 8-oxo-dG (a measure of DNA break frequency), or anti-inflammatory cytokine levels in the blood relate to cognitive processes impaired in normal aging. Results from this study may provide insight into effects of the protective FOXO3 variant on the rate of brain aging, and may elucidate biological mechanisms of aging and eventually identify interventions to increase the number of years of healthy living.